Association of a Novel Mutation in the Plasmodium Falciparum Chloroquine Resistance Transporter With Decreased Piperaquine Sensitivity

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2017 Sep 22

PMID 28931241

Citations 76

Authors

Sonia Agrawal

Kara A Moser

Lindsay Morton

Michael P Cummings

Ankita Parihar

Ankit Dwivedi

Amol C Shetty

Elliott F Drabek

Christopher G Jacob

Philipp P Henrich

Christian M Parobek

Krisada Jongsakul

Rekol Huy

Michele D Spring

Charlotte A Lanteri

Suwanna Chaorattanakawee

Chanthap Lon

Mark M Fukuda

David L Saunders

David A Fidock

Jessica T Lin

Jonathan J Juliano

Christopher V Plowe

Joana C Silva

Shannon Takala-Harrison

Affiliations

Soon will be listed here.

Abstract

Background: Amplified copy number in the plasmepsin II/III genes within Plasmodium falciparum has been associated with decreased sensitivity to piperaquine. To examine this association and test whether additional loci might also contribute, we performed a genome-wide association study of ex vivo P. falciparum susceptibility to piperaquine.

Methods: Plasmodium falciparum DNA from 183 samples collected primarily from Cambodia was genotyped at 33716 genome-wide single nucleotide polymorphisms (SNPs). Linear mixed models and random forests were used to estimate associations between parasite genotypes and piperaquine susceptibility. Candidate polymorphisms were evaluated for their association with dihydroartemisinin-piperaquine treatment outcomes in an independent dataset.

Results: Single nucleotide polymorphisms on multiple chromosomes were associated with piperaquine 90% inhibitory concentrations (IC90) in a genome-wide analysis. Fine-mapping of genomic regions implicated in genome-wide analyses identified multiple SNPs in linkage disequilibrium with each other that were significantly associated with piperaquine IC90, including a novel mutation within the gene encoding the P. falciparum chloroquine resistance transporter, PfCRT. This mutation (F145I) was associated with dihydroartemisinin-piperaquine treatment failure after adjusting for the presence of amplified plasmepsin II/III, which was also associated with decreased piperaquine sensitivity.

Conclusions: Our data suggest that, in addition to plasmepsin II/III copy number, other loci, including pfcrt, may also be involved in piperaquine resistance.

Citing Articles

Low prevalence of copy number variation in pfmdr1 and pfpm2 in Plasmodium falciparum isolates from southern Angola.

Duarte D, Manuel F, Dias A, Sacato E, Taleingue E, Daniel E Malar J. 2025; 24(1):5.

PMID: 39794826 PMC: 11720348. DOI: 10.1186/s12936-024-05240-2.

Dihydroartemisinin-Piperaquine Combination in the Treatment of Uncomplicated Malaria: Update on Clinical Failures in Africa and Tools for Surveillance.

Delandre O, Pradines B, Javelle E J Clin Med. 2024; 13(22).

PMID: 39597971 PMC: 11594973. DOI: 10.3390/jcm13226828.

Incomplete growth inhibition following piperaquine treatment translates into increased parasite viability in the parasite reduction ratio assay.

Walz A, Sax S, Scheurer C, Tamasi B, Maser P, Wittlin S Front Cell Infect Microbiol. 2024; 14:1396786.

PMID: 38746786 PMC: 11091375. DOI: 10.3389/fcimb.2024.1396786.

Strong positive selection biases identity-by-descent-based inferences of recent demography and population structure in Plasmodium falciparum.

Guo B, Borda V, Laboulaye R, Spring M, Wojnarski M, Vesely B Nat Commun. 2024; 15(1):2499.

PMID: 38509066 PMC: 10954658. DOI: 10.1038/s41467-024-46659-0.

Assessing emergence risk of double-resistant and triple-resistant genotypes of Plasmodium falciparum.

Li E, Nguyen T, Tran T, Zupko R, Boni M Nat Commun. 2024; 15(1):1390.

PMID: 38360803 PMC: 10869733. DOI: 10.1038/s41467-024-45547-x.

References

Maung Lwin K, Imwong M, Suangkanarat P, Jeeyapant A, Vihokhern B, Wongsaen K . Elimination of Plasmodium falciparum in an area of multi-drug resistance. Malar J. 2015; 14:319. PMC: 4537587. DOI: 10.1186/s12936-015-0838-5. View

Denis M, Tsuyuoka R, Lim P, Lindegardh N, Yi P, Top S . Efficacy of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in northwest Cambodia. Trop Med Int Health. 2006; 11(12):1800-7. DOI: 10.1111/j.1365-3156.2006.01739.x. View

Van Tyne D, Park D, Schaffner S, Neafsey D, Angelino E, Cortese J . Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum. PLoS Genet. 2011; 7(4):e1001383. PMC: 3080868. DOI: 10.1371/journal.pgen.1001383. View

Price A, Patterson N, Plenge R, Weinblatt M, Shadick N, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006; 38(8):904-9. DOI: 10.1038/ng1847. View

Amaratunga C, Lim P, Suon S, Sreng S, Mao S, Sopha C . Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infect Dis. 2016; 16(3):357-65. PMC: 4792715. DOI: 10.1016/S1473-3099(15)00487-9. View

Noedl H, Se Y, Schaecher K, Smith B, Socheat D, Fukuda M . Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008; 359(24):2619-20. DOI: 10.1056/NEJMc0805011. View

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

Miotto O, Almagro-Garcia J, Manske M, MacInnis B, Campino S, Rockett K . Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet. 2013; 45(6):648-55. PMC: 3807790. DOI: 10.1038/ng.2624. View

Parobek C, Lin J, Saunders D, Barnett E, Lon C, Lanteri C . Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia. Proc Natl Acad Sci U S A. 2016; 113(50):E8096-E8105. PMC: 5167194. DOI: 10.1073/pnas.1608828113. View

10.

Wang Z, Cabrera M, Yang J, Yuan L, Gupta B, Liang X . Genome-wide association analysis identifies genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum from China-Myanmar border. Sci Rep. 2016; 6:33891. PMC: 5046179. DOI: 10.1038/srep33891. View

11.

Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois A, Khim N . A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2013; 505(7481):50-5. PMC: 5007947. DOI: 10.1038/nature12876. View

12.

Van der Auwera G, Carneiro M, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A . From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics. 2014; 43:11.10.1-11.10.33. PMC: 4243306. DOI: 10.1002/0471250953.bi1110s43. View

13.

Witkowski B, Duru V, Khim N, Ross L, Saintpierre B, Beghain J . A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study. Lancet Infect Dis. 2016; 17(2):174-183. PMC: 5266792. DOI: 10.1016/S1473-3099(16)30415-7. View

14.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A . The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-303. PMC: 2928508. DOI: 10.1101/gr.107524.110. View

15.

Denis M, Tsuyuoka R, Poravuth Y, Narann T, Seila S, Lim C . Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia. Trop Med Int Health. 2006; 11(9):1360-6. DOI: 10.1111/j.1365-3156.2006.01690.x. View

16.

Leang R, Taylor W, Mey Bouth D, Song L, Tarning J, Char M . Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment. Antimicrob Agents Chemother. 2015; 59(8):4719-26. PMC: 4505193. DOI: 10.1128/AAC.00835-15. View

17.

Chaorattanakawee S, Saunders D, Sea D, Chanarat N, Yingyuen K, Sundrakes S . Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance. Antimicrob Agents Chemother. 2015; 59(8):4631-43. PMC: 4505231. DOI: 10.1128/AAC.00366-15. View

18.

Barrett J, Fry B, Maller J, Daly M . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2004; 21(2):263-5. DOI: 10.1093/bioinformatics/bth457. View

19.

Rutvisuttinunt W, Chaorattanakawee S, Tyner S, Teja-Isavadharm P, Se Y, Yingyuen K . Optimizing the HRP-2 in vitro malaria drug susceptibility assay using a reference clone to improve comparisons of Plasmodium falciparum field isolates. Malar J. 2012; 11:325. PMC: 3489509. DOI: 10.1186/1475-2875-11-325. View

20.

DePristo M, Banks E, Poplin R, Garimella K, Maguire J, Hartl C . A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011; 43(5):491-8. PMC: 3083463. DOI: 10.1038/ng.806. View